EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

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Studies were performed to define the accumulation of cytokines and other mediators of inflammation in experimental models of inflammation in normal human subjects and in patients with abnormalities of host defenses or inflammation. Skin blisters created by suction and heat were used to study local inflammation in the skin. The kinetics of the appearance of inflammatory cytokines in the blister fluid revealed mediators appearing early (C5a, LTB4, IL1beta, and IL-8) and mediators appearing late at 12 hrs or later (TNF-alpha and GM-CSF) with IL-1alpha and IL-2 not detected. Studies of skin blisters in patients with abnormal inflammatory responses revealed dramatic increases in TNF-alpha in patients with acute vasculitis in association with Wegeners granulomatosis, in patients with systemic mastocytosis, and in the syndrome of hyperimmunoglobulin E and recurrent infections. Increases in TNF-alpha correlated well with disease activity suggesting that targeting drug development for modulation of this cytokine will have specific merit in these disease states. Normal blister exudate neutrophils synthesize large amounts of IL-6, IL-8, and TNF-alpha compared with control peripheral blood neutrophils. Studies of normals and patients with excessive inflammation revealed a tight linear relationship between the level of IL-8 and the number of inflammatory neutrophils in the exudate. Exudate neutrophils synthesize IL-8 which is stored in a compartment different from specific or azurophil granules, but is co-eluted with an alkaline phosphatase rich plasma membrane fraction. E. coli endotoxin was administered to normal volunteers and patients in accordance with a long standing NIAID protocol. Increased plasma levels of TNF-alpha, TNF-alpha receptor, IL- 1alpha receptor antagonist, IL-6 and IL-8 occurred within 4h and G-CSF increased by 6 h, but not changes in IL-1alpha, IL-1beta, IL-2, IL-3, IL- 4, IL-10, interferon-gamma, TGF-beta or C5a were seen. There was a striking increase in circulating E-selectin by 2-4 h after endotoxin administration which was dose related suggesting that E-selectin may be predictive of those patients with endotoxemia who will progress to shock. Definition of specific mediators that are abnormal in different disease states is important for developing therapies. In other studies the long term monitoring of patients with chronic granulomatous disease of childhood who are receiving interferon gamma as infectious prophylaxis indicated no adverse effects. In other studies interferon-gamma was shown to be useful in enhancing host defense against infection with mycobacteria including MAI.